The present invention relates to novel compounds, which are 3-acyl and acylamido derivatives; including derivatives of hydroxamic acids or amide derivatives of ureas, carbonyl esters, carboxy esters, or sulfones and esters thereof, of 2-carboxyindoles. The present invention also relates to novel compounds which are 2-carboxyindoles having an unsaturated carboxylic acid group and derivatives thereof at the 3 position. The novel compounds of the present invention are useful as pharmaceutical agents and, therefore, the present invention also relates to methods for the preparation of the compounds, to pharmaceutical compositions, and to methods of use therefor. More specifically, the compounds of the present invention are useful in the treatment of neurodegenerative disorders including cerebrovascular disorders as well as in the treatment of schizophrenia or epilepsy; and as analgesics and anxiolytics.
Excessive excitation by neurotransmitters can cause the degeneration and death of neurons. It is believed that this degeneration is in part mediated by the excitotoxic actions of the excitatory amino acids (EAA) glutamate and aspartate at N-methyl-D-aspartate (NMDA), .alpha.-amino-3-hydroxy-5-methyl-isoxazole propionic acid (AMPA), and kainate receptor. This excitotoxic action is responsible for the loss of neurons in cerebrovascular disorders such as cerebral ischemia or cerebral infarction resulting from a range of conditions, such as thromboembolic or hemorrhagic stroke, cerebral vasospasm, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery and cerebral trauma.
There are no specific therapies for these neurodegenerative diseases; however, compounds which act specifically as antagonists of EAA receptors and in particular the NMDA receptor complex, either competitively or noncompetitively, offer a novel therapeutic approach to these disorders: R. Schwarcz and B. Meldrum, The Lancet 140 (1985); B. Meldrum in "Neurotoxins and Their Pharmacological Implications" edited by P. Jenner, Raven Press, New York (1987); D. W. Choi, Neuron 1:623 (1988). Confirmation of the protective effects of noncompetitive NMDA antagonists in various pharmacological models of neurodegenerative disorders have appeared in the literature: J. W. McDonald, F. S. Silverstein, and M. V. Johnston, Eur. J. Pharmacol. 140:359 (1987); R. Gill, A. C. Foster, and G. N. Woodruff, J. Neurosci. 7:3343 (1987); S. M. Rothman, J. H. Thurston, R. E. Hauhart, G. D. Clark, and J. S. Soloman, Neurosci. 21:673 (1987); M. P. Goldbert, P-C. Pham, and D. W. Choi, Neurosci. Lett. 80:11 (1987); L. F. Copeland, P. A. Boxer, and F. W. Marcoux, Soc. Neurosci. Abstr. 14 (part 1):420 (1988); J. A. Kemp, A. C. Foster, R. Gill, and G. N. Woodruff, TIPS 8:414 (1987); R. Gill, A. C. Foster, and G. N. Woodruff J. Neurosci. 25:847 (1988); C. K. Park, D. G. Nehls, D. I. Graham, G. M. Teasdale, and J. M. McCulloch, Ann. Neurol. 24:543 (1988); G. K. Steinburg, C. P. George, R. DeLaPlaz, D. K. Shibata, and T. Gross, Stroke 19:1112 (1988); J. F. Church, S. Zeman, and D. Lodge, Anesthesiology 69:702 (1988).
U.S. Pat. No. 4,960,736 discloses certain 2-carboxylic indole derivatives useful as excitatory (EAA) amino acid antagonists and EP Application Numbers 90107633.1 and 90108337.8 also disclose certain 2-carboxylic indole derivatives for use to treat neurotoxic injury or neurodegenerative diseases known to be caused by or accelerated by certain EAAs found in the central nervous system (CNS).
Each of these references differs from the present invention by the hydroxamide, amide, urea amide, ester amide or sulfonamide substituent on an acyl group of the 2-carboxyindoles as disclosed herein. Also not taught by these references is the use of unsaturated acids and derivatives thereof, for example, hydroxamide, amide, urea amide, ester amide, or sulfonamide products such as now found in the present invention. Therefore, each of the aforementioned publications differs from the present invention.